Peptidylarginine deiminase (PAD) enzymes epigenetically regulate gene expression in pituitary lactotrope cells; yet, the physiological consequences of this on lactotrope function during pregnancy and lactation are unknown. This gap in knowledge is important because lactotrope remodeling during pregnancy is absolutely required to maximize prolactin synthesis, initiate lactation, and stimulate breastmilk production. This is a highly relevant medical question because breastfeeding has profound health benefits for both the mother and infant. Our long- term goal is to understand hormone mediated epigenetic control of lactation at the molecular level. The objective of this proposal is to show that PAD catalyzed histone citrullination is a novel regulator of miRNA biogenesis that mediates 17?-estradiol (E2) induced lactotrope population changes during pregnancy. Our data demonstrate that PAD expression is highest in lactotropes from late pregnant mice and that these enzymes suppress expression of a riboprotein termed DGCR8 microprocessor complex subunit (DGCR8) which is critical for miRNA biogenesis. We propose a model in which E2 stimulates PAD expression, and then histone citrullination suppresses miRNA biogenesis. With decreased miRNAs, mRNAs encoding important proliferative, growth factor and gap junction proteins increase to drive lactotrope remodeling during pregnancy. Our central hypothesis is that E2 increases expression of PAD enzymes which then citrullinate histones to suppress miRNA processing in lactotropes during pregnancy. The central hypothesis will be tested with the following specific aims: (1) Determine the mechanism by which E2 regulates PAD expression and histone citrullination in lactotropes; (2) Determine the role of DGCR8 in miRNA biogenesis in lactotropes. The work is significant because it is an important step to characterize a completely novel, unexplored mechanism that is essential for lactotrope population changes during pregnancy and ultimately lactation. The proposed research is innovative because investigating histone citrullination induced miRNA biogenesis represents a new and substantial departure from current studies in the field.